Project Summary/Abstract
Neurons are among the most energetically-demanding cell types in the body, and as such, heavily rely on
the output of mitochondria to fuel their basic functionality. Because of this, a disproportionate number of genes
whose dysfunction is associated with neurodegenerative disease are related to mitochondrial function. Of
particular importance to neuronal health and survival is the process of degrading mitochondria. Despite this
link, little is known about the cell biological pathways that mediate the breakdown of mitochondria in neurons
within their native, physiological environment in nervous tissue. The overall goal of this proposal is gain a
further understanding of the various pathways neurons utilize to break down their mitochondria.
Within nervous tissue, neurons get support from a specialized cell type known as glial cells. It has recently
been discovered that knock down of the ataxia-associated gene Vps13D leads to the strong inhibition of a
neuron’s ability to break down their mitochondria via a pathway known as mitophagy. In response to this robust
inhibition, neurons adaptively induce an alternative means of mitochondrial breakdown that involves the
transfer of damaged mitochondria to supportive glial cells for their ultimate degradation. With the discovery of
this new pathway of mitochondrial degradation, the mentored phase of this proposal will use the robust
phenotype associated with loss of Vps13D to guide the development of tools for studying non-cell autonomous
mitochondrial degradation in neurons in vivo. This work will also uncover the conditions that lead to the
induction of this transcellular neuron to glia mitochondrial breakdown.
In the independent phase of this proposal, the goal will be to use these newly developed tools to gain a
mechanistic understanding of how mitochondria are released from neurons. Using the powerful genetic tools
available in fruit fly research, this Aim will test out candidate molecules with a history of mediating intercellular
mitochondrial trafficking in other cell types to determine whether they participate in neuron to glial
mitochondrial transfer.
Finally, the goal of the another focus of this proposal in the independent phase will be to determine if this
newly discovered, alternative form of mitochondrial degradation become adaptively more prevalent during the
course of aging as levels of autophagy decrease. Then, this Aim will test the cellular and functional
consequences of disrupting neuron-to-glial transfer of mitochondrial in this susceptible population of aged
neurons.
With the completion of the research proposed in this application, the applicant will have carved out a
distinctive niche for an independent research career focusing on the cell biology of transcellular mitochondrial
degradation in neurons.